Division of Anatomic and Molecular Pathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Department of Pharmacology, Jiangsu University School of Medicine, Zhenjiang, Jiangsu Province, 212013, PR China.
Nat Commun. 2023 Sep 22;14(1):5923. doi: 10.1038/s41467-023-41629-4.
Treatment of osteoporosis commonly diminishes osteoclast number which suppresses bone formation thus compromising fracture prevention. Bone formation is not suppressed, however, when bone degradation is reduced by retarding osteoclast functional resorptive capacity, rather than differentiation. We find deletion of deubiquitinase, BRCA1-associated protein 1 (Bap1), in myeloid cells (Bap1), arrests osteoclast function but not formation. Bap1 osteoclasts fail to organize their cytoskeleton which is essential for bone degradation consequently increasing bone mass in both male and female mice. The deubiquitinase activity of BAP1 modifies osteoclast function by metabolic reprogramming. Bap1 deficient osteoclast upregulate the cystine transporter, Slc7a11, by enhanced H2Aub occupancy of its promoter. SLC7A11 controls cellular reactive oxygen species levels and redirects the mitochondrial metabolites away from the tricarboxylic acid cycle, both being necessary for osteoclast function. Thus, in osteoclasts BAP1 appears to regulate the epigenetic-metabolic axis and is a potential target to reduce bone degradation while maintaining osteogenesis in osteoporotic patients.
治疗骨质疏松症通常会减少破骨细胞数量，从而抑制骨形成，从而影响骨折预防。然而，当通过延缓破骨细胞功能吸收能力而不是分化来减少骨降解时，骨形成不会受到抑制。我们发现，破骨细胞中的去泛素酶 BRCA1 相关蛋白 1（Bap1）缺失会阻止破骨细胞的功能但不会阻止其形成。Bap1 破骨细胞无法组织其细胞骨架，这对于骨降解至关重要，因此会增加雄性和雌性小鼠的骨量。BAP1 的去泛素酶活性通过代谢重编程来修饰破骨细胞功能。Bap1 缺陷型破骨细胞通过增强其启动子上 H2Aub 的占有率而上调胱氨酸转运蛋白 Slc7a11。SLC7A11 控制细胞内活性氧水平，并将线粒体代谢物从三羧酸循环中转移，这两者对于破骨细胞功能都是必需的。因此，在破骨细胞中，BAP1 似乎调节表观遗传代谢轴，是减少骨质疏松症患者骨降解同时维持成骨的潜在靶点。
